EP0574769A1 - Verwendung spezifischer gegenanionen zum Verändern der Löslichkeit von Tetrazoliumsalzen - Google Patents

Verwendung spezifischer gegenanionen zum Verändern der Löslichkeit von Tetrazoliumsalzen Download PDF

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Publication number
EP0574769A1
EP0574769A1 EP93108863A EP93108863A EP0574769A1 EP 0574769 A1 EP0574769 A1 EP 0574769A1 EP 93108863 A EP93108863 A EP 93108863A EP 93108863 A EP93108863 A EP 93108863A EP 0574769 A1 EP0574769 A1 EP 0574769A1
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EP
European Patent Office
Prior art keywords
tetrazolium
tetrazolium salt
alkyl
salt
salts
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP93108863A
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English (en)
French (fr)
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EP0574769B1 (de
Inventor
Joel M. Blatt
Robert P. Hatch
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Bayer Corp
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Bayer Corp
Miles Inc
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Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • Tetrazolium salts such as 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl tetrazolium (INT) are very useful in the measurement of analytes which can be converted to an equivalent concentration of NADH due to the reduction of the tetrazolium salt to its corresponding formazan which reduction can be accurately measured by colorimetric means.
  • a typical reagent system for determining glucose concentration in body fluids is based on reductive chemistry wherein the primary components are hexokinase (HK), adenosine triphosphate (ATP), glucose-6-phosphate dehydrogenase (G-6-PDH), diaphorase, nicotinamideadenine dinucleotide (NAD) and a tetrazolium salt as indicator.
  • HK hexokinase
  • ATP adenosine triphosphate
  • G-6-PDH glucose-6-phosphate dehydrogenase
  • NAD nicotinamideadenine dinucleotide
  • tetrazolium salt as indicator.
  • hexokinase catalyzes the reaction in which, in the presence of glucose, a phosphate radical is taken from ATP thereby converting it to adenosine diphosphate to form glucose-6-phosphate which is oxidized in the presence of NAD and G-6-PDH thereby reducing NAD to NADH.
  • the NADH in the presence of diaphorase as electron acceptor, reduces the colorless tetrazolium salt to its colored formazan counterpart thereby providing a detectable response.
  • the reaction steps represent the determination of NADH as an indirect means of determining the glucose concentration in the test sample:
  • the utility of tetrazolium salts in such systems for detecting such analytes is proportional to their solubility in water or suitable organic solvents. This is particularly true in the case of dry reagent diagnostic test devices, such as those in which a tetrazolium salt is dissolved in a polar organic solvent for impregnation into a carrier matrix such as paper or a polymer matrix or dissolved in an aqueous solution of a film forming polymer such as gelatin.
  • Tetrazolium salt indicators are typically used with gelatin film and other dry reagent formulations which employ diaphorase or a chemical mediator in the color generating step.
  • the concentration of indicator must be in the range of 0.05M to 0.15M or more.
  • United States patent 1,892,019 discloses the increased water solubility of benzylmorphine after it is reacted with alkyl sulphonic acid, e.g. methane or ethanesulfonic acid, by formation of the corresponding salt.
  • U.S. patent 4,334,071 discloses the enhancement of the solubility of 17-cyclobutylmethyl-3-hydroxy -8 ⁇ -methyl-6-methylene morphinane by converting its chloride salt to the corresponding methanesulfonate.
  • United States patent 3,655,382 discloses tetrazolium thiazolium salts in which the counteranion can be chloride, iodide, bromide, thiocyanate, thiosulfate, sulfate, paratoluenesulfonate, methylsulfate, ethyl sulfate, nitrate, acetate, perchlorate, perborate, sulfite, hydroxide or carbonate.
  • the counteranion can be chloride, iodide, bromide, thiocyanate, thiosulfate, sulfate, paratoluenesulfonate, methylsulfate, ethyl sulfate, nitrate, acetate, perchlorate, perborate, sulfite, hydroxide or carbonate.
  • Counteranions such as those derived from higher alkylbenzenesulfonic acids, e.g. dodecylbenzenesulfonic acid or a higher alkyl sulfuric acid ester such as lauryl sulfate are disclosed.
  • the present invention involves certain salts of tetrazolium compounds which exhibit unexpectedly high solubility in polar solvents.
  • These salts include a counteranion of the formula: or
  • R is an organic radical suitable for increasing the solubility of the tetrazolium salt in an aqueous or non-aqueous polar solvent.
  • R is a straight or branched chain alkyl of 1 to 7 carbon atoms or phenyl.
  • a diagnostic test device comprising a reagent system incorporated into a carrier matrix containing one or more of the sulfonate and/or phosphonate tetrazolium salts.
  • the tetrazolium salts of the present invention can be represented by the formula: wherein X ⁇ is the counteranion as defined above, R1 and R3 are phenyl groups and R2 is phenyl or 2-thiazolyl.
  • X ⁇ is the counteranion as defined above
  • R1 and R3 are phenyl groups and R2 is phenyl or 2-thiazolyl.
  • the phenyl and optional thiazol groups can be substituted or unsubstituted.
  • R1, R3 and optionally R2 can be represented by, but are not limited to, the formula: wherein the Y groups (Y1, Y2, Y3 or Y4) which are the same or different can be, for example, alkoxy, aryloxy, alkyl, amido, alkylamido, arylamido, alkylthio, arylthio, halo, hydrogen, hydroxy, carbamoyl, carbalkoxy, carboxyl, cyano, nitro, sulfo, sulfonamido, sulfamoyl, trialkylamino or ureido groups.
  • the Y groups Y1, Y2, Y3 or Y4
  • the Y groups which are the same or different can be, for example, alkoxy, aryloxy, alkyl, amido, alkylamido, arylamido, alkylthio, arylthio, halo, hydrogen, hydroxy, carbamoyl,
  • R2 is a thiazole group
  • it can be unsubstituted or substituted.
  • the thiazole group is represented by the formula: where R4 and R5 are hydrogen or some other substituent.
  • the R1 and R3 moieties of the tetrazolium salt are as described above and R2 is a thiazole group in which R4 and R5 together form a benzo ring which is substituted or unsubstituted;
  • R4 is carboxyl, carbalkoxy, carbamoyl, or cyano and R5 is alkyl or chloro;
  • R4 is alkyl or aryl and R5 is carboxyl, carbalkoxy, carbaryloxy, carbamoyl or cyano;
  • R4 is di- or trifluoroalkyl wherein the fluoro substituents are on the carbon adjacent to the thiazolyl residue; or one or both of R4 and R5 are substituted or unsubstituted phenyl, and if only one is substituted phenyl, the other is hydrogen or alkyl.
  • those tetrazolium cations which are particularly useful in the context of the present invention are those in which R4 and R5 together form
  • the salts of the present invention are most conveniently prepared by interaction of less soluble salts of the tetrazolium compound with an anion exchange resin which is converted to its alkyl or benzene sulfonate or phosphonate form.
  • This procedure is preferably carried out in the presence of an ion exchange resin due to the ease of purification which is rendered by this technique.
  • the ion exchange resin one can simply stir the tetrazolium salt in a slurry of the resin followed by filtration, concentration and crystallization to obtain the pure salt.
  • Alternative procedures which involve stirring the less soluble tetrazolium salt with the alkyl or benzene sulfonic or phosphoric acid or their salts can also be employed.
  • an ion exchange resin when an ion exchange resin is used the excess sulfonate or phosphate tetrazolium salt is attached to the resin and can be separated from the reaction mass by filtration.
  • a slurry of 5.5 g of tetrazolium salt, e.g. the tetrafluoroborate, and 50 g of moist resin is stirred in 300 mL of methanol for 2-4 hours.
  • the mixture is warmed to 40°C.
  • the mixture is filtered and then concentrated to a gum like residue whereupon the product precipitates after stirring with ethyl acetate.
  • salts are prepared by stirring the appropriate formazan with isoamylnitrate in the presence of 48% fluoroboric acid in acetic acid and filtering the product. Optionally, if the product does not precipitate, ether is added to force precipitation. Nitrate salts are prepared in a similar manner in the absence of fluoroboric acid.
  • the enhanced water solubility of these salts is significant since it facilitates the inclusion of adequate quantities of the tetrazolium salt into thin films of water soluble polymers such as gelatin.
  • the high methanol solubility of the benzenesulfonate is also significant.
  • the use of non-aqueous solvents in preparing the previously mentioned carrier matrix films is important because it enables one to deposit the indicator into the matrix from non-aqueous solutions wherein the liquid phase is a non-solvent for the reagent system used to create the detectable response.
  • Typical carrier matrixes include bibulous materials such as filter paper or a nonbibulous material such as a membrane of a polymerized substance or a combination thereof.
  • methanol solubility of MTM is substantially increased by converting it to the methane- or propanesulfonate.
  • the solubility of this tetrazolium compound decreases when it is converted to the benzenesulfonate but is still substantially greater than the nitrate.
  • no improvement in methanol solubility was observed for the paratoluene and naphthalene salts of these tetrazolium compounds.
  • the tetrazolium salts of the present invention are particularly suitable for use in analytical test devices of the type previously mentioned since the solubility of the salt can be tailored to the particular device being fabricated.
  • the organic moiety, R in the foregoing general formula is lower alkyl, preferably methyl, in order to provide a tetrazolium salt with the requisite hydrophilic properties.
  • the R group is selected to render the salt soluble in polar organic solvents, which are not good solvents for the other reagents, to facilitate application of the tetrazolium indicator from its solution in the polar organic solvent either before or after the other reagents have been applied to the substrate from their aqueous solution.
  • Methanol is a particularly good solvent for certain tetrazolium indicators wherein the R group in the counteranion is phenyl.
  • the strip was treated with 5 1/2 liters of an aqueous solution containing 100 mM/L adenosine triphosphate. After the aqueous impregnation, 1 liter of the aqueous solution remained which was found to contain 3 mM of the tetrazolium salt which was extracted from the treated membrane. The solution also contained some formazan which was not quantified. Assuming that the formazan was also 3 mM, there was recovered an equivalent of 6 millimoles of the tetrazolium salt which had been extracted from the membrane during the aqueous impregnation, representing a loss of 1.875 percent.
  • Impregnation of the fabric with methanolic, ethanolic or other alcoholic solutions of the indicator in which the counteranion was nitrate or tetrafluoroborate was unsuccessful due to the low solubility of these salts in alcohol. Concentrations of these salts comparable to that achieved with methanol was achieved using a 1:1 mixture of dimethylformamide and methanol. However, the use of dimethylformamide is undesirable on an industrial manufacturing scale since it is an established liver and kidney toxin.
  • tetrazolium salt from its methanol solution facilitates the use of a two dip procedure for applying the indicator in a first dip with the enzymes and other water soluble constituents of the reagent system in a second dip from their aqueous solutions without rehydrating the already deposited tetrazolium salt.
  • a more hydrophilic organic radical such as that of methanesulfonate
  • the tetrazolium salt is rendered water soluble so that the entire reagent system including the indicator can be applied in a single dip.
  • Application from separate dips as in this example is preferred in order to minimize interaction between the reagents during the application of the reagent system to the substrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP93108863A 1992-06-15 1993-06-02 Verwendung spezifischer gegenanionen zum Verändern der Löslichkeit von Tetrazoliumsalzen Expired - Lifetime EP0574769B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US898317 1986-08-20
US07/898,317 US5250695A (en) 1992-06-15 1992-06-15 Use of specific counteranions to modify the solubility of tetrazolium salts

Publications (2)

Publication Number Publication Date
EP0574769A1 true EP0574769A1 (de) 1993-12-22
EP0574769B1 EP0574769B1 (de) 1996-04-17

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EP93108863A Expired - Lifetime EP0574769B1 (de) 1992-06-15 1993-06-02 Verwendung spezifischer gegenanionen zum Verändern der Löslichkeit von Tetrazoliumsalzen

Country Status (8)

Country Link
US (1) US5250695A (de)
EP (1) EP0574769B1 (de)
JP (1) JPH06107644A (de)
AT (1) ATE136892T1 (de)
AU (1) AU646185B2 (de)
CA (1) CA2084036C (de)
DE (1) DE69302224T2 (de)
ES (1) ES2086825T3 (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075008A1 (en) * 2002-03-05 2003-09-12 Bayer Healthcare Llc Absorbing organic reagent into diagnostic test devices by formation of amine salt complexes
US7378255B2 (en) 2003-01-28 2008-05-27 Roche Diagnostics Operations, Inc. Fluorimetric determination of analytes by an intramolecular quencher-fluorophore conjugate
US8546580B2 (en) 2005-03-01 2013-10-01 Life Technologies Corporation Chemical probe compounds that become fluorescent upon reduction, and methods for their use
WO2016026959A1 (en) 2014-08-22 2016-02-25 Roche Diagnostics Gmbh Redoxindicators

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69320224T2 (de) * 1992-03-17 1999-05-06 Unitika Ltd Verfahren und Reagenz zur enzymatischen Analyse
US5360595A (en) * 1993-08-19 1994-11-01 Miles Inc. Preparation of diagnostic test strips containing tetrazolium salt indicators
JP2002122584A (ja) * 2000-10-16 2002-04-26 Fuji Photo Film Co Ltd 乾式分析素子及びその製造方法
DE10304448A1 (de) 2003-02-04 2004-08-12 Roche Diagnostics Gmbh Fluorimetrische Bestimmung von Analyten durch Amin-N-Oxide als Redoxindikatoren
JP5592058B2 (ja) 2005-01-14 2014-09-17 バイエル・ヘルスケア・エルエルシー 水溶性テトラゾリウム塩
WO2018051822A1 (ja) * 2016-09-14 2018-03-22 テルモ株式会社 ２－置換ベンゾチアゾリル－３－置換フェニル－５－置換スルホ化フェニル－２ｈ－テトラゾリウム塩、ならびに当該塩を含む生体成分濃度測定用試薬および当該塩を用いる生体成分濃度の測定方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655382A (en) * 1970-02-25 1972-04-11 Eastman Kodak Co Processes for converting zero-valent metals photographic images to formazan dye images
US4221864A (en) * 1977-02-01 1980-09-09 Konishiroku Photo Industry Co., Ltd. Light-sensitive silver halide photographic materials
US4334071A (en) * 1981-02-02 1982-06-08 Miles Laboratories, Inc. 17-Cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinane methanesulfonate
EP0100217A2 (de) * 1982-07-23 1984-02-08 Wako Pure Chemical Industries, Ltd. Verfahren zur quantitativen Bestimmung eines mit Oxidase behandelten Substrates
US5036000A (en) * 1986-12-16 1991-07-30 Enzymatics, Inc. Threshold color control system

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1892019A (en) * 1932-12-27 osi basel
DE3611227A1 (de) * 1986-04-04 1987-10-08 Boehringer Mannheim Gmbh Verfahren und reagenz zur bestimmung von substraten oder enzymaktivitaeten
CA2049209C (en) * 1990-09-19 1992-03-20 Jurgen Kocher Phenyl-substituted 2-thiazolyl tetrazolium salt indicators

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655382A (en) * 1970-02-25 1972-04-11 Eastman Kodak Co Processes for converting zero-valent metals photographic images to formazan dye images
US4221864A (en) * 1977-02-01 1980-09-09 Konishiroku Photo Industry Co., Ltd. Light-sensitive silver halide photographic materials
US4334071A (en) * 1981-02-02 1982-06-08 Miles Laboratories, Inc. 17-Cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinane methanesulfonate
EP0100217A2 (de) * 1982-07-23 1984-02-08 Wako Pure Chemical Industries, Ltd. Verfahren zur quantitativen Bestimmung eines mit Oxidase behandelten Substrates
US5036000A (en) * 1986-12-16 1991-07-30 Enzymatics, Inc. Threshold color control system

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075008A1 (en) * 2002-03-05 2003-09-12 Bayer Healthcare Llc Absorbing organic reagent into diagnostic test devices by formation of amine salt complexes
US7563621B2 (en) 2002-03-05 2009-07-21 Siemens Healhcare Diagnostics Inc Absorbing organic reagents into diagnostic test devices by formation of amine salt complexes
US7378255B2 (en) 2003-01-28 2008-05-27 Roche Diagnostics Operations, Inc. Fluorimetric determination of analytes by an intramolecular quencher-fluorophore conjugate
US8546580B2 (en) 2005-03-01 2013-10-01 Life Technologies Corporation Chemical probe compounds that become fluorescent upon reduction, and methods for their use
WO2016026959A1 (en) 2014-08-22 2016-02-25 Roche Diagnostics Gmbh Redoxindicators
EP3757096A1 (de) 2014-08-22 2020-12-30 Roche Diagnostics GmbH Redoxindikatoren

Also Published As

Publication number Publication date
DE69302224T2 (de) 1996-09-19
ATE136892T1 (de) 1996-05-15
CA2084036A1 (en) 1993-12-16
CA2084036C (en) 2001-02-20
JPH06107644A (ja) 1994-04-19
AU646185B2 (en) 1994-02-10
AU2732292A (en) 1993-12-16
US5250695A (en) 1993-10-05
EP0574769B1 (de) 1996-04-17
ES2086825T3 (es) 1996-07-01
DE69302224D1 (de) 1996-05-23

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